Disorders of iron metabolism are among the most prevalent diseases in humans. Iron deficiency is thought to affect greater than one billion people worldwide, particularly women and children. The anemia of chronic inflammation, resulting from disordered systemic iron distribution, is the most common form of anemia in hospitalized patients as well as patients with common chronic diseases such as heart failure, rheumatoid arthritis, renal disease, and cancer. The inherited iron overload disorders collectively known as hereditary hemochromatosis are similarly common;the prevalence of a single mutant allele, HFE<C282Y>, that confers a risk for iron overload is as much as 10% in individuals of Northern European descent. The transmembrane transport of iron and copper, another essential micronutrient, are substantially dependent upon protein reductases to maintain the metals in the oxidation state required by the predominant cell surface and endosomal metal importers. For example, erythroid cells are uniquely dependent upon the transferrin cycle for iron acquisition. Transferrin binds ferric (Fe3+), whereas ferrous (Fe2+) iron is the species that is transported across the endosomal membrane. This necessitates an intra-endosomal reduction step. We recently identified the major erythroid transferrin cycle endosomal ferrireductase, Steap3, by positionally cloning the mouse iron deficiency anemia mutant nm1054. Steap3 is one of a family of four homologous proteins in mammalian genomes, three of which we have recently demonstrated have not only ferrireductase, but also cuprireductase, activity. In this grant we will investigate the roles of the Steap proteins in metal metabolism through gene expression, cross-complementation, murine deficiency phenotypic analyses, and protein association studies.